Technical Field
The present disclosure relates to cyclic phosphates and cyclic phosphoramidates, pharmaceutical compositions containing such compounds, and their use in the treatment of neurologic disorders (such as pantothenate kinase-associated neurodegeneration).
Description of the Related Art
Pantothenate kinase-associated neurodegeneration (PKAN) is a form of neurodegeneration with brain iron accumulation (NBIA) that causes extrapyramidal dysfunction (e.g., dystonia, rigidity, choreoathetosis) (A. M. Gregory and S. J. Hayflick, “Neurodegeneration With Brain Iron Accumulation,” Orphanet Encyclopedia, September 2004). PKAN is thought to be a genetic disorder resulting from lack of the enzyme pantothenate kinase, which is responsible for the conversion of pantothenic acid (vitamin B5) to 4′-phosphopantothenic acid. 4′-Phosphopantothenic acid is subsequently converted into Coenzyme A (CoA) (as shown below) (R. Leonardi, Y.-M. Zhang, C. O. Rock, and S. Jackowski, “Coenzyme A: Back In Action,” Progress in Lipid Research, 2005, 44, 125-153).

In particular, pantothenic acid is converted to 4′-phosphopantothenic acid via the enzyme pantothenate kinase (PANK), which is converted to 4′-phosphopantothenoylcysteine via the enzyme 4′-phosphopantothenoylcysteine synthase (PPCS), and subsequently decarboxylated to 4′-phosphopantetheine via 4′-phosphopantothenoylcysteine decarboxylase (PPCDC). 4′-phosphopantetheine is then appended to adenosine by the action of phosphopantethine adenyltransferase (PPAT) to afford dephospho CoA, which is finally converted to coenzyme A (CoA) via dephospho-CoA kinase (DPCK).
Classic PKAN usually presents in a child's first ten to fifteen years, though there is also an atypical form that can occur up to age 40. PKAN is a progressively degenerative disease that leads to loss of musculoskeletal function with a devastating effect on quality of life.
One approach to treating PKAN could be to administer 4′-phosphopantothenic acid. This approach has been mentioned in the literature, but it has been recognized that the highly charged molecule would not be able to permeate the lipophilic cell membrane (C. J. Balibar, M. F. Hollis-Symynkywicz, and J. Tao, “Pantethine Rescues Phosphopantothenoylcysteine Synthetase And Phosphopantothenoylcysteine Decarboxylase Deficiency In Escherichia Coli But Not In Pseudomonas aeruginosa,” J. Bacteriol., 2011, 193, 3304-3312).